Hyperhomocysteinemia is a common metabolic disorder that causes significant increase in the total level of plasma homocysteine. In spite of the FDA-mandated fortification of food with folic acid, as an attempt to lower homocysteine level, the incidence of hyperhomocysteinemia in the elderly population is still quite large. This is mainly due to lowered nutritional absorption and decreased metabolic function with advanced age. Epidemiological studies have established that hyperhomocysteinemia is a risk factor for neurological diseases. However, the direct impact of hyperhomocysteinemia on the outcome of neurological diseases is still not known. Our findings now show that ischemic insult under hyperhomocysteinemic condition leads to concurrent activation of a novel signaling pathway involving GluN2A-NMDAR activation that in conjunction with the canonical pathway exacerbates ischemic brain injury. The long-term goal of our research is to develop therapeutic interventions for reducing the adverse effect of hyperhomocysteinemia on cerebral ischemia and related neurodegenerative disorders. The objective of this particular application is to delineate whether GluN2A-NMDAR mediated neuroinflammation plays a central role in the exacerbation of ischemic brain damage under hyperhomocysteinemic condition. The central hypothesis is that under hyperhomocysteinemic condition, GluN2A-NMDAR-mediated excessive release of the pro-inflammatory mediators MCP-1 and PGE2 from neurons results in augmentation of post-ischemic microglial activation and peripheral immune cell infiltration. The proposed studies will use (1) primary neuronal cultures to delineate the signaling cascade, downstream of homocysteine-GluN2A-NMDAR stimulation, involved in the increased expression and release of MCP-1 and PGE2 from neurons; (2) hyperhomocysteinemic rat and mice, as well as a series of conditional knockout mice to evaluate the role GluN2A-NMDAR in post-ischemic augmentation of inflammatory response in hyperhomocysteinemic animals; and (3) magnetic resonance imaging (MRI) and a battery of behavioral tests to evaluate the long-term efficacy of post-ischemic inhibition of GluN2A-NMDAR signaling pathway in reducing brain damage in hyperhomocysteinemic animals. The proposed research is significant since it will fill a knowledge gap that is critical for future designing of novel therapeutic targets to mitigate the severity of stroke outcome under hyperhomocysteinemic condition.